The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

Abstract

Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually.While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. The Oncologist 2015; 20:1058-1068Implications for Practice: This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in‐situ hybridisation

“…Most studies, including endometrial and ovarian CCC, applied IHC without ISH, often with 2+/3+ scores considered positive, and none have compared IHC antibodies (most use HercepTest). Although no data on endometrial CCC are specifically available, IHC/ISH discordance is known to occur in endometrial carcinoma in general, with higher overexpression than amplification rates . On ovarian CCC, only one study implemented IHC and ISH on all cases, reporting 14% HER2‐positivity (six of 50 cases) with perfect IHC/ISH concordance (2+/3+ classified positive with HercepTest) .…”

“…Although no data on endometrial CCC are specifically available, IHC/ISH discordance is known to occur in endometrial carcinoma in general, with higher overexpression than amplification rates. [24][25][26] On ovarian CCC, only one study implemented IHC and ISH on all cases, reporting 14% HER2-positivity (six of 50 cases) with perfect IHC/ISH concordance (2+/3+ classified positive with Her-cepTest). 34 In our study, IHC/ISH concordance was poor in both endometrial and ovarian CCC, even when we excluded IHC 2+ scores (in which discordance with ISH can be expected due to the equivocal nature of 2+).…”

“…[14][15][16][17][18][19][20][21][22] In endometrial and ovarian cancer, HER2-positivity varies considerably: 17-80% in endometrial and 8-66% in ovarian carcinoma. [23][24][25] Specific data on CCC are scarce, with 14-67% HER2-positivity reported in small patient cohorts (often n < 10). [25][26][27][28][29][30][31][32][33][34][35][36][37] Results of anti-HER2 therapy in endometrial and ovarian carcinoma to date are inconsistent.…”

siRNA: A Promising New Tool for Future Breast Cancer Therapy

“…The human epidermal growth factor receptor 2 (HER2) gene, also known as HER2/neu, ERBB2, or CD340, is associated with poor breast cancer prognosis; the HER2 gene is amplified and the HER2 protein overexpressed in approximately 20% of all breast cancer cases. [31,33] As suggested by experimental evidence, the amplification of HER2 appears to lead to malignant transformation. [36] Breast cancer cells may possess from 25-50 copies of the HER2 gene and consequently a 40-100 times increase in the expression of HER2, ultimately culminating in up to 2 million HER2 proteins being expressed at the cell surface at a time.…”

“…Many genes associated with the development of breast cancer, including BRCA1, BRCA2, HER2, and p53, could serve as potential targets for this treatment. [27,33,49]…”